The overall aim of this research is to obtain new marine natural products with bioactivity against solid tumors, especially colon, breast, prostate, and lung cancers. These are the tumors that are resistant to most of the known anticancer drugs and are responsible for 67 percent of the annual cancer deaths in the US. The work will be carried out through a collaboration between the University of California, Santa Cruz (UCSC) Marine Natural Products team and the Experimental Therapeutics Investigators, moving in January 1999 from Wayne Sate University (WSU) Cancer Center to the Henry Ford Cancer Center (HFCC) (Detroit). The specific aims of this grant are: (a) To use bioassay-guided isolations in the discovery of new marine natural product anticancer candidates. (b) To employ an in vitro mammalian cell assay in order to focus on agents with "cellular selectivity" for solid tumors. (c) To investigate under-explored sponge taxonomic orders such as the Choristida, Dendroceratida, Hadromerida, Haplosclerida, Lithistida, Poeciloslcerida, and Spirophorida. (d) To develop a library of marine sponge-derived fungal cultures whose saltwater fermentation products will be explored for their potential to act as selective cytotoxic agents. (e) To continue work on leads obtained from prior research involving potent tumor selective alkaloids and oxygen heterocycles which include: sponge compounds-cyclocinamide A (6), ethyldidehydroplakortide Z (22), milnamide B (31), reticulatine A (41c), methylnuapapuanoate A (44), and a sponge-fungal derived metabolite-tenuazonic acid (50). (f) To continue, but on a limited basis, the study of sponge taxa (especially Theonella and Stellata) which might have a broadened scope of natural products owing to the presence of symbionts. (g) To complete the structure elucidation of active compounds. (h) To preliminarily develop new anticancer leads for future clinical trials by using in vivo evaluation in mouse models to examine the in vitro active compounds. Lead compounds will be identified by a multistaged process. Indo-Pacific sponges will be explored. The leads (above) from past research will be examined by scale-up isolation to complete in vivo studies and analogs will also be sought from other extracts. There are 32 extracts on hand which are solid tumor selective that will be pursued to isolate their active constituents. Annual expeditions will generate more than 100 new organisms for study which should provide five to ten new compounds for investigation. Sponge-derived fungi will be grown in saltwater culture and those with solid tumor selective extracts will be candidates for isolation work. An adjunct to the HFCC in vitro mammalian cell assays will be "bench-top assays" carried out at UCSC.